Dual-site molecular glues for enhancing protein-protein interactions of the CDK12-DDB1 complex.

Protein-protein interactions (PPIs) stabilization with molecular glues plays a crucial role in drug discovery, albeit with significant challenges. In this study, we propose a dual-site approach, targeting the PPI region and its dynamic surroundings. We conduct molecular dynamics simulations to identify critical sites on the PPI that stabilize the cyclin-dependent kinase 12 - DNA damage-binding protein 1 (CDK12-DDB1) complex, resulting in further cyclin K degradation. This exploration leads to the creation of LL-K12-18, a dual-site molecular glue, which enhances the glue properties to augment degradation kinetics and efficiency. Notably, LL-K12-18 demonstrates strong inhibition of gene transcription and anti-proliferative effects in tumor cells, showing significant potency improvements in MDA-MB-231 (88-fold) and MDA-MB-468 cells (307-fold) when compared to its precursor compound SR-4835. These findings underscore the potential of dual-site approaches in disrupting CDK12 function and offer a structural insight-based framework for the design of cyclin K molecular glues.

Discovery of a highly potent NPAS3 heterodimer inhibitor by covalently modifying ARNT.

Neuronal PAS domain protein 3 (NPAS3), a basic helix-loop-helix PER-ARNT-SIM (bHLH-PAS) family member, is a pivotal transcription factor in neuronal regeneration, development, and related diseases, regulating the expression of downstream genes. Despite several modulators of certain bHLH-PAS family proteins being identified, the NPAS3-targeted compound has yet to be reported. Herein, we discovered a hit compound BI-78D3 that directly blocks the NPAS3-ARNT heterodimer formation by covalently binding to the aryl hydrocarbon receptor nuclear translocator (ARNT) subunit. Further optimization based on the hit scaffold yielded a highly potent Compound 6 with a biochemical EC50 value of 282 ± 61 nM and uncovered the 5-nitrothiazole-2-sulfydryl as a cysteine-targeting covalent warhead. Compound 6 effectively down-regulated NPAS3's transcriptional function by disrupting the interface of NPAS3-ARNT complexes at cellular level. In conclusion, our study identifies the 5-nitrothiazole-2-sulfydryl as a cysteine-modified warhead and provides a strategy that blocks the NPAS3-ARNT heterodimerization by covalently conjugating ARNT Cys336 residue. Compound 6 may serve as a promising chemical probe for exploring NPAS3-related physiological functions.

A patent review of PRMT5 inhibitors to treat cancer (2018 - present).

INTRODUCTION: Protein arginine methyltransferase 5 (PRMT5) belongs to type II arginine methyltransferases. Since PRMT5 plays an essential role in mammalian cells, it can regulate various physiological functions, including cell growth and differentiation, DNA damage repair, and cell signal transduction. It is an epigenetic target with significant clinical potential and may become a powerful drug target for treating cancers and other diseases. AREAS COVERED: This review provides an overview of small-molecule inhibitors and their associated combined treatment strategies targeting PRMT5 in cancer treatment patents published since 2018, and also summarizes the progress made by several biopharmaceutical companies in the development, application, and clinical trials of small-molecule PRMT5 inhibitors. The data in this review come from WIPO, UniProt, PubChem, RCSB PDB, National Cancer Institute, and so on. EXPERT OPINION: Many PRMT5 inhibitors have been developed with good inhibitory activities, but most of them lack selectivities and are associated with adverse clinical responses. In addition, the progress was almost all based on the previously established skeleton, and more research and development of a new skeleton still needs to be done. The development of PRMT5 inhibitors with high activities and selectivities is still an essential aspect of research in recent years.